This proposal is submitted in response to the new NIDDK announcement (PA-14- 058) calling for development of new diagnostic, monitoring, and therapeutics technologies for the complications of type 1 diabetes (T1D). An estimated 15-25% of the 25.8 million diabetic patients in this country will develop diabetic foot ulcers (DFU) at some point in their lives. Currently, even the best available treatments achieve only a 50% healing rate for these wounds-and this healing is often only temporary with a high chance of recurring. Although the causes of non-healing chronic wounds are multifactorial, one critical pathophysiology is ischemia-a deficient blood supply. Ischemia may not be the initiating factor for DFU, because most ulcers start from a combination of neuropathy, pressure loading, and/or trauma. However, tissue ischemia is the main cause that hinders healing-wounds do not heal in tissue that does not bleed, whereas they always heal in tissue that bleeds extensively. The most critical consequence of ischemia is a decreased cellular energy supply because energy is required in every aspect of the wound healing process from protein synthesis to cell migration, proliferation, and functioning. Our company has developed a technique to encapsulate Mg-ATP into very small unilamellar lipid vesicles for intracellular delivery (ATP-vesicles or VitaSolTM). When we use this new technique in animal wound models, not only healing is enhanced, but also produces an unprecedented result: Granulation tissue starts to appear in less than 24 hours. It continues to grow and covers the whole wound within 3-5 days. Massive cell accumulation and proliferation occur not only on the wound wall, but also in the wound cavity where no blood supply exists. We have never seen this phenomenon in humans or any other land animals, nor has it been reported in the literature by any other treatment strategy. The effect seems even more pronounced in long-term (12 months or longer) diabetic plus ischemic wounds. Although the granulation tissue growth is rapid, it shows a self-limiting feature, which results in no hypertrophic scar formation or any other overgrowth even after 2 years. Like many other wound care specialists, when we first saw this unprecedented result, we did not believe it because it seemed too good to be true. However, this novel healing response has been confirmed in more than 130 rabbits (over 1040 wounds). In this phase I proposal, we will compare VitaSolTM with Regranex, the only FDA- approved prescription growth factor for wound care, in a diabetic wound model without skin contraction, and perform a preliminary toxicity study. The accomplishment of these two goals will bring the project one step closer to IND application. Our technique of intracellular energy delivery has consistently been viewed as innovative. If successful, it will provide an inexpensive and easy to use dressing for DFU treatment, something not yet achieved despite thousands of dressings developed or proposed. The potential impact is high.